Abstract The Myeloproliferative Neoplasm Research Consortium (MPN-RC) is an inter-active group of laboratory and clinical scientists from 11 institutions throughout North America who will continue to work in a coordinated fashion to develop therapeutic strategies intended to improve the survival of patients with the myeloproliferative neoplasm (MPN), myelofibrosis (MF). The MPNs which also include polycythemia vera (PV), and essential thrombocythemia (ET) are clonal hematological malignancies which affect at least 300,000 individuals in the United States and are recognized as rare diseases by the National Cancer Institute (NCI). The Consortium has received continuous NCI funding since 2006 to elucidate the pathogenetic mechanisms underlying MPNs and address the unmet clinical needs of MPN patients. In the present application, we have chosen to focus our efforts on MF since it is the MPN with the shortest survival and at present allogeneic hematopoietic stem cell transplantation is the only approach which substantially alters its natural history. During the last decade, MF patients have received enormous clinical benefit from the widespread use of the JAK1/2 inhibitor, ruxolitinib, which is the first drug approved for the treatment of MF patients. Unfortunately, this drug (and others in the class) does not substantially halt disease progression and offers minimal improvement in survival. The limitations of this class of drugs can be attributed to an inability to eliminate MF hematopoietic stem cells (HSC) and/or disarm supportive microenvironments. To improve MF patient survival, we hypothesize that drugs capable of effectively depleting MF HSCs but sparing their normal counterparts be utilized. These drugs would act by directly targeting malignant HSCs and/or by correcting their tumor promoting micro-environments. Lessons learned from these studies will be useful to scientists and clinicians studying a large number of other cancers. The overall goal of the MPN-RC is to employ the complementary skills and efforts of its scientifically diverse membership to generate the scientific foundation for novel therapeutic strategies which will be evaluated in well-constructed, independent, investigator-initiated early phase clinical trials. To achieve these goals the following Specific Aims will be pursued: Specific Aim 1: To develop the scientific rationale for the use of therapeutic agents which deplete or eliminate MF stem cells by directly targeting malignant MPN stem cells. Specific Aim 2: To target aberrant inflammatory signaling and dysregulated gene expression in MF cells and in the microenvironment which drives disease progression. Specific Aim 3: To rationally design and rapidly execute preclinical studies and investigator-initiated phase I/II clinical trials with novel agents, including biomarker based studies embedded within our clinical trial platform to document efficacy of novel MF therapies. Specific Aim 4: Actively and dynamically maintain the scientific research and clinical research infrastructure needed to support and coordinate the performance of all laboratory investigations and clinical trials planned by the MPN-RC.